Islet transplantation (ITx), especially with the emerging potential of xenotransplantation, holds significant promise for the treatment of type 1 diabetes (T1D). There are, however, major challenges that remain prior to its larger scale, cost-effective application. Hypoxia is a leading stress post-transplantation and is estimated to cause the death of approximately 40-50% of transplanted islets. Effective protection of transplanted islets from hypoxia-induced death (HID) has the potential to greatly enhance the success rate of ITx. Preliminary research in our labs demonstrated that alpha- and gamma-tocopherol and their succinate esters offer remarkable protection to porcine and human islets from HID at 24 hrs. Furthermore alpha- and gamma-tocopherol, when administered by injection starting 24 h pretransplantation, improved the cure rates of nude mice transplanted with the same islet mass as untreated controls by ~70%. Oral administration, if effective, would provide a preferred, more practical and safer alternative to injections. The objectives of this Phase I STTR are to: (i) Determine whether the succinate esters of alpha- plus gamma-tocopherol (which may provide additional advantages either as injectable or oral supplements) are equally or more effective than the corresponding tocopherols at the same and/or a lower dose when administered by intraperitoneal injections to diabetic nude mice transplanted with porcine islets;and (ii) Determine whether an oral administration protocol is an effective and efficacious alternative to injections. Because alpha- and gamma-tocopherol and alpha-tocopheryl succinate are approved for human consumption, this technology, if effective, can be rapidly evaluated for safety and incorporated in the clinical treatment of T1D. In Phase II, the effective compounds will be formulated for stability and tested for efficacy in preclinical islet transplantation models including nonhuman primates, which are well established at the University of Minnesota. The successful completion of the proposed work may lead to a significant, potentially breakthrough contribution in the development of islet transplantation as a safe and cost effective therapy for T1D by markedly improving islet viability post-transplantation. PUBLIC HEALTH RELEVANCE: This STTR can lead to a very safe product, which increases substantially the success rate of islet transplantation. This product can have reaching effects in advancing the practical use of islet transplantation in treating Type 1 diabetes. In addition to improving the quality of life and productivity of these patients, this product can help reduce the cost of health care.